Cellular Response to Ionizing Radiation: A MicroRNA Story.

MicroRNAs (miRNAs) represent a class of small non-coding RNA molecules that regulate gene expression at the post-transcriptional level. They play a crucial role in diverse cellular pathways. Ionizing radiation (IR) is one of the most important treatment protocols for patients that suffer from cancer and affects directly or indirectly cellular integration. Recently it has been discovered that microRNA-mediated gene regulation interferes with radio-related pathways in ionizing radiation. Here, we review the recent discoveries about miRNAs in cellular response to IR. Thoroughly understanding the mechanism of miRNAs in radiation response, it will be possible to design new strategies for improving radiotherapy efficiency and ultimately cancer treatment.

onizing radiation (IR) is widely used for the treatment of cancer. IR directly damage cellular components or generate reactive oxygen (ROS) and nitrogen (RNS) species that can disrupt atomic structure of macromolecules (1). DNA is the primary target for cell damage from IR (2). There are two major types of IR including photons (x-rays and γ-rays), which are most widely used in radiotherapy and particle radiation (electrons, protons, neutrons, carbon ions, α-particles, and βparticles). In X and γ-rays, most of the radiation effects are through free radicals whereas in particle radiation, direct damage of DNA is more important.
In this review, the word "ionizing radiation" refers to all these radiations and their effects. A series of signaling pathways begin in cells following exposure to IR that may arrest the cell cycle and repair the damage or induce apoptosis if damage is extensive or in some cases enhance cell division and resistance to cytotoxic stresses (3 occurs between the miRNA and target mRNA, Argonaute 2 (Ago2) (an RNase enzyme), cleaves the mRNA, otherwise translation is repressed without degradation of target mRNA (7)(8)(9). So far, about 1500 miRNAs have been identified in human.
A single miRNA can bind many mRNAs and multiple miRNAs can target a single mRNA.
Therefore, there is a complex regulatory network between miRNAs and their target genes (10,11).
IR triggers several biochemical and signaling events and alters expression of many genes involved in cell cycle regulation, checkpoints, apoptosis, and signal transduction pathways (12). Since miRNAs participate in control of an estimated >30% of all human genes, it is logical that miRNAs be also involved in the regulation of IR-induced gene expression. In this review, we illustrate the detailed regulatory mechanisms of miRNAs in modulating cellular response to ionizing radiation from diverse aspects.

IR-induced DNA damage response (DDR)
The main toxic biological effect of IR is DNA single (SSB) or double (DSB) strand break.
Cells are very sensitive to DNA breaks especially at late G2, and during M phase (13,14). Several genes upregulate after DNA break. The product of these genes could be categorized in three groups including sensors, transducers, and effectors. The final effect of all these processes is cell cycle arrest and DNA repair, or if the damage is extensive, apoptosis will occur (15). The first group of molecules that detect DNA breaks are sensors. The and Rad50/Mre11 (16)(17)(18). Recently with discovery of miRNAs, a new layer of complexity has been added to IR signaling (19). However, there are newly discovered pathways

MiRNAs and radiation induced signal transduction pathways
IR not only causes cell death, but also has potential of enhancing proliferation in the surviving fraction of cells (43,44). IR damages DNA and generates ROS that the later products in addition to activation of p53 and ATM, are able to activate growth factor receptors in the plasma membrane (44

Conclusion
Although it is not long time from the discovery of miRNAs, it have been cleared that these molecules have some roles in several cellular processes such as stress response, apoptosis, cellular differentiation and proliferation, cellular response to ionizing radiation and also these molecules have aberrant expression in a variety of diseases (55,56). The main effect of IR on cells is DNA damage that results to cell cycle arrest or cell death especially in dividing cells. IR can also induce proliferation in the surviving fraction of cells. It has been discovered that miRNAs have fundamental role in several IR induced cell signaling events. In this review some miRNAs involved in cellular response to ionizing radiation have been discussed briefly; However, there are still many questions to be addressed. With thorough knowledge about the role of miRNAs in radiation response, it will be possible to design new strategies for improving radiotherapy efficiency and ultimately cancer treatment.

Conflict of interest:
None declared.